Both estrogen and the neurotrophins influence neural organization. The estrogen receptor, which mediates the biological response of the hormone, is expressed at high levels in the brain during development, and estrogen has been shown to promote growth in the developing nervous system, in vivo [39, 67, 77, 93, 94], in vitro [97-101] and in oculo [78]. Although estrogen receptor expression is more restricted in adulthood, estrogen continues to affect neuronal structure, physiology and gene expression in specific adult steroid targets [19, 21, 30, 68, 83].
Estrogen regulates transcription of a variety of structural proteins [38, 62, 94], steroid, peptide and neurotransmitter receptors [19, 21, 63], as well as hormones and neuropeptides [83, 110]. The estrogen receptor is a member of the superfamily of steroid/thyroid hormone/Vitamin D.sub.3 /retinoic acid receptors, capable of activating genes by directly binding DNA sites containing hormone-specific regulatory elements [4, 24, 79]. An estrogen response element (ERE) has been identified in several estrogen-responsive genes including vitellogenin [50], c-fos [109], prolactin [107] and b-luteinizing hormone [89], suggesting that, in some instances, steroid effects may be mediated through direct activation of relevant genes. Alternatively, as in extra-neural targets such as MCF-7 mammary tumor cells [20] and the uterus [73, 76], estrogen-inducible genes may be regulated secondarily, or consequent, to the action of estrogen on other endogenous transcription-regulating growth factors or their receptors [99, 102].
The currently identified members of the neurotrophin family of growth factors, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophins-3 (NT-3) and -4/5 (NT-4/5), share marked similarities in their conserved sequences and structural domains and all bind to the pan-neurotrophin receptor, p75.sup.NGFR, although they differ in their spatial and temporal patterns of neural expression and function [2, 12, 47, 65, 81]. Ligand specificity and signal transduction requires the neurotrophins to associate with appropriate members of the trk proto-oncogene receptor tyrosine kinase family (trkA, trkB, trkC) of membrane bound receptors [48, 53, 91, 92].
Both NGF and estrogen have been shown: 1) to promote survival and specific patterns of differentiation in their neuronal targets [55, 103], 2) to regulate the expression of primary (early) response genes such as c-fos and c-jun [17, 57, 108, 109, 111], 3) to regulate the activity of cholinergic enzymes in the developing [1, 4, 61] and adult basal forebrain [32, 43, 59, 60]. It has been shown that in neurons of the developing forebrain [72, 105, 106], estrogen receptors colocalize with p75.sup.NGFR mRNA and protein as well as mRNA for trkA (whose encoded protein binds NGF) [15, 48, 75] and trkB (whose encoded protein binds BDNF and NT-4/5) [45, 91, 92], indicating a biological substrate for possible interactions between estrogen and the neurotrophins. Analysis of the identified promoter region [88] of the p75.sup.NGFR [90, 105, 106] and 5'-region flanking the breakpoint of the trkA gene [90] indicates the presence of sequences with a high degree of homology to the putative vitellogenin and c-fos EREs, which is further consistent with the hypothesis that, in some instances, estrogen may regulate responsiveness to neurotrophins.
Co-localization of estrogen and neurotrophin receptor mRNA and protein [72, 105, 106] suggested that estrogen sensitivity may be a more general feature of neurotrophin targets. This hypothesis was tested in a previous study investigating the presence of estrogen receptor systems in a prototypic peripheral target of NGF, the dorsal root ganglion (DRG) of the adult female rat [90]. DRG neurons are dependent on NGF for their survival during development [2, 23, 46, 96] and in adulthood, following injury [16, 56, 82]. Both estrogen receptor mRNA and estrogen binding were found to be present in adult DRG neurons in vivo [90] . Moreover, in these neurons estrogen resulted in a two to three-fold increase in trkA mRNA and a transient decrease in p75.sup.NGFR mRNA.